Genetics of the IL-1 Gene Cluster
The IL-1 gene cluster is on the long arm of chromosome 2 (2q13) and contains at least the genes for IL-1.alpha. (IL-1A), IL-1.beta. (IL-1B), and the IL-1 receptor antagonist (IL-1RN), within a region of 430 Kb (Nicklin, et al. (1994) Genomics, 19:382-4). The agonist molecules, IL-1.alpha. and IL-1.beta., have potent pro-inflammatory activity and are at the head of many inflammatory cascades. Their actions, often via the induction of other cytokines such as IL-6 and IL-8, lead to activation and recruitment of leukocytes into damaged tissue, local production of vasoactive agents, fever response in the brain and hepatic acute phase response. All three IL-1 molecules bind to type I and to type II IL-1 receptors, but only the type I receptor transduces a signal to the interior of the cell. In contrast, the type II receptor is shed from the cell membrane and acts as a decoy receptor. The receptor antagonist and the type II receptor, therefore, are both anti-inflammatory in their actions.
Inappropriate production of IL-1 plays a central role in the pathology of many autoimmune and inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disorder, psoriasis, and the like. In addition, there are stable inter-individual differences in the rates of production of IL-1, and some of this variation may be accounted for by genetic differences at IL-1 gene loci. Thus, the IL-1 genes are reasonable candidates for determining part of the genetic susceptibility to inflammatory diseases, most of which have a multifactorial etiology with a polygenic component.
Certain alleles from the IL-1 gene cluster are known to be associated with particular disease states. For example, IL-1RN (VNTR) allele 2 has been shown to be associated with osteoporosis (U.S. Pat. No. 5,698,399), nephropathy in diabetes mellitus (Blakemore, et al. (1996) Hum. Genet 97(3):369-74), alopecia areata (Cork, et al., (1995) J. Invest. Dermatol. 104(5 Supp.):15S-16S; Cork et al. (1 996) Dermatol Clin 14:671-8), Graves disease (Blakemore, et al. (1995) J. Clin. Endocrinol. 80(1):111-5), systemic lupus erythematosus (Blakemore, et al. (1994) Arthritis Rheum. 37:1380-85), lichen sclerosis (Clay, et al. (1994) Hum. Genet 94:407-10), and ulcerative colitis (Mansfield, et al. (1994) Gastoenterol. 106(3):637-42)).
In addition, the IL-1A allele 2 from marker -889 and IL-1B (TaqI) allele 2 from marker +3954 have been found to be associated with periodontal disease (U.S. Pat. No. 5,686,246; Kormman and diGiovine (1998) Ann Periodont 3:327-38; Hart and Kornman (1997) Periodontol 2000 14:202-15; Newman (1997) Compend Contin Educ Dent 18:881-4; Kornman et al. (1997) J. Clin Periodontol 24:72-77). The IL-1A allele 2 from marker -889 has also been found to be associated with juvenile chronic arthritis, particularly chronic iridocyclitis (McDowell, et al. (1995) Arthritis Rheum. 38:221-28). The IL-1B (TaqI) allele 2 from marker +3954 of IL-1B has also been found to be associated with psoriasis and insulin dependent diabetes in DR3/4 patients (di Giovine, et al. (1995) Cytokine 7:606; Pociot, et al. (1992) Eur J. Clin. Invest. 22:396-402). Additionally, the IL-1RN (VNTR) allele 1 has been found to be associated with diabetic retinopathy (see U.S. Ser. No. 09/037472, and PCT/GB97/02790). Furthermore allele 2 of IL-1RN (VNTR) has been found to be associated with ulcerative colitis in Caucasian populations from North America and Europe (Mansfield, J. et al., (1994) Gastroenterology 106:637-42). Interestingly, this association is particularly strong within populations of ethnically related Ashkenazi Jews (PCT W097/25445).